The present study was performed to evaluate the effect of glimepiride, Vanadyl Sulfate (VOSO4) or their combination on glycemic status and oxidative stress in STZ-diabetic rats and to investigate the possible mechanism of action of these drugs. Another aim of this study is to determine whether there is a possible interaction between certain chosen trace element (VOSO4) and glimepiride as representative to oral hypoglycemic agents. Treatment of STZ-diabetic animals with glimepiride (10 mg/kg, p.o.) or VOSO4 (15 mg/kg, i.p.) decreased serum glucose level and increased liver glycogen content. Glimepiride increased serum insulin level and glucose (6 mmol/L)-stimulated insulin secretion from isolated rat pancreatic islets. Vanadyl sulfate did not affect serum insulin level or glucose (6 mmol/L)-stimulated insulin secretion from isolated rat pancreatic islets. Glimepiride and VOSO4 increased plasma GSH level, plasma SOD level and decreased serum TBARS level. Combination of VOSO4 with glimepiride did not improve the effect of glimepiride alone on any of the measured parameters when given in the selected doses indicating no significant interaction between these two drugs on the selected parameters. It could be concluded that concurrent administration of VOSO4 with glimepiride does not produce any additive effect on any of the measured parameters. Therefore, VOSO4 can be taken safely as a micronutrient in diabetic patient treated with glimepiride without fear of any serious reactions.